主办:上海医药工业研究院
   中国药学会
   中国化学制药工业协会
ISSN 1001-8255   CN 31-1243/R   ZYGZEA

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    Perspectives & Review
  • Perspectives & Review
    ZHOU Jianfen, CHAI Zhilan, XIE Cao, LU Weiyue
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    Exosomes are nanoscale(40 - 100 nm) vesicles secreted by cells that play an important role in intercellular material transport and signal communication. Exosomes are similar in size and function to synthetic nanoparticles, but as natural endogenous transport carriers, they have the advantages such as low toxicity, no immunogenicity, and good permeability. So, exosomes may become promising drug delivery vehicles. Herein, we provide a comprehensive understanding of the properties and applications of exosomes, including their biogenesis, composition, isolation, drug loading methods for small molecules and biologic macromolecules, and typical examples in drug delivery and therapy. Furthermore, their advantages compared with other nanoparticles and potential in tumor therapy are also discussed. Nevertheless, some challenges remain regarding the loading and targeting of exosomes for which more researches are necessary, and have been discussed in this review.
  • Perspectives & Review
    DU Ruoxi, SHEN Tiantian, ZHANG Yilan
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    Temperature-time indicators(also known as the temperature-sensitive labels) can record the temperature change trajectory during the cold chain transportation, storage, and usage of pharmaceutical products, which are suitable for intelligent packaging of medicines. Temperature-sensitive labels intuitively convert the temperature change trajectory into clear visual information through color changes. For indeed, the temperature-time indicator containing 10,12-pentacosadiynoic acid is blue in initial state(0 ℃). While temperature increases, the indicator slides to the other end along the capillary fiber and its color gradually changes to red. Therefore, people can recognize whether the medicine has experienced an inappropriate temperature through the visual information, then judge whether the shelf life and quality safety of the medicine are affected. Temperature-sensitive labels can be divided into critical temperature indicators (CTI), critical temperature/time indicators(CTTI) and time-temperature indicators(TTI). Among them, TTI can be divided into reversible and irreversible types. According to the working principle, TTI can also be divided into diffusionbased, polymerization-based and biological enzyme-catalyzed degradation-based types. However, the expensive price of TTI makes low popularity in domestic, and there are only a few related researches. This paper summarizes the research progress of irreversible TTI with different working principles and prospects the future development in the pharmaceutical field as well.
  • Perspectives & Review
    LIU Xiaoya, JIANG Changzhao, GAO Wenyan, YE Jincui
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    In recent years, as a new drug delivery system with advantages of small particle size, enhanced permeation, high solubility and easy to prepare, microemulsion has been widely studied in the development of pharmaceutical preparations. This paper summarizes the related references of microemulsion and microemulsion-based transdermal preparations applied to different types of drugs at home and abroad in recent years, and introduces the formulation composition, formation mechanism, advantages and disadvantages of microemulsion and research cases in various therapeutic fields. Microemulsion has broad application prospects in the field of transdermal preparations because of its advantages of promoting transdermal penetration, improving stability, prolonging therapeutic duration and reducing skin irritation.
  • ZHU Bingfeng, CHEN Yinghui, ZHANG Guimin, LIU Zhiyu, LIU Yizhou
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    The residual water in raw materials and reaction system is not conducive to the synthesis of chemical drugs, and water content in bulk drugs and pharmaceutical preparations affects the stability, physical and chemical properties, dissolution and pharmacological effects. Therefore, residual water is almost a must-test item in the synthesis, and it is important to strictly control the water content in the reaction system by effective water removal methods. To provide some references for water removal in drug synthesis, this paper reviews the existence forms of water, common dewatering agents and dehydrating agents as well as their action principles and abilities of removing water. The applications of water removal in the synthesis of chemical drugs are briefly introduced.
  • Perspectives & Review
  • Perspectives & Review
    ZHAI Xiaoyu, ZHANG Yilan
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    Extractables and leachables study on drug packaging materials is an important part of compatibility research. A sample of extractables and leachables is a complex system containing trace amounts of volatiles, semivolatiles, non-volatiles and trace element impurities, which should be performed using orthogonal, proprietary, and sensitive analytical methods to analyze thoroughly. This paper systematically describes the sources of extractables and leachables, the application of chromatographic mass spectrometry on the study of extractables and leachables, and the strategy of unknown compound identification.
  • Perspectives & Review
    HUANG Lu, GU Shuangxi
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    In this paper, we summarize the research progress of small molecular drugs for the potential treatment of COVID-19 at home and abroad, and focus on detailed analysis and interpretation of the patents of hot drugs such as lopinavir/ritonavir, chloroquine phosphate, remdesivir in clinical trials, in order to provide useful references for clinicians, pharmaceutical companies, and research institutions engaged in SARS-CoV-2 research and clinical application.
  • Paper
  • Paper
    BAI Wenqin, SONG Chuanling, TANG Zhenbo, WANG Youguo, ZHANG Guimin
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    The synthetic process of cladribine(1) for treating multiple sclerosis was improved in this report. 1-Chloro-2-deoxy-3,5-di-O-p-toluoyl-α-D-ribofuranoside(5) was obtained from D-2-deoxy-ribose(2) by methylation, hydroxyl protection and chlorination. The compound 5 reacted with 2,6-dichloropurine in the presence of the phase transfer catalyst, tris(3,6-dioxaheptyl)amine, and potassium hydroxide to give 2,6-dichloro-9-(2-deoxy-3,5-di-O-ptoluoyl- β-D-furanyl)purine nucleoside(6). The latter was heated in a saturated ammonia/methanol solution, involving the 6-amination and de-protection to obtain 1 in a total yield of 52% and ee>99%. In this process, the phase transfer catalyst effectively inhibited the production of the α-isomer, and this reaction without sodium alkoxide avoided the production of purine base metal salts and the impurity of 2-chloro-7-(2-deoxy-3,5-di-O-p-toluoyl-β-D-furanyl)adenine nucleoside(7). The purification methods both for intermediates and product were simple and without the use of column chromatography. This process was suitable for industrial production.
  • Paper
    GUO Jianfeng, CHEN Yi, LI Li'e, TIAN Luanyuan, WANG Miao
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    The synthetic process of the antiviral drug rilpivirine hydrochloride(1) was improved. Ethyl formyl acetate(2) reacted with S-methylisothioure(3) to give 2-(methylthio)-4-hydroxyl-pyrimidine(4). Compound 4 reacted with 4-aminobenzonitrile(5) in ethylene glycol dimethyl ether in the presence of methanesulfonic acid to give 4-[(4-hydroxypyrimidin-2-yl)amino]benzonitrile(6), and the reaction temperature decreased from 200 ℃ to 110 - 120 ℃. Compound 6 reacted with HBr/CH3COOH to obtain 4-[(4-bromopyrimidin-2-yl)amino]benzonitrile(7). 4-Bromo-2,6-dimethylaniline(8) reacted with acrylonitrile(9) in the presence of palladium acetate and tris(Omethylphenyl) phosphine instead of 10% Pd/C to give (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile(10), by which the cis-isomer was reduced from 20% to 0.60%. Meanwhile, compound 10 was purified by recrystallization instead of column chromatography in the work-up, so that the yield of this step was increased from 48% to 87%. Compound 7 was condensed with 10 under the action of 1,1,3,3-tetramethylguanidine(TMG) as acid binding agent, and the title compound in a purity of 99.92% was obtained via a salt formation with oxalic acid, and the content of cis-isomer was reduced to 0.08%. The improved process was simple and convenient with a total yield of 52%(based on 2).
  • Paper
    CHU Yanjun, WANG Chunyan, LIU Ge, TI Wenli, ZHANG Guimin
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    The synthetic process of miriplatin(1) was improved. Tetradecanoic acid(2) reacted with NaOH in ethyl acetate/pure water and purified by static crystallization to give sodium tetradecanoate(3). Compound 3 reacted with oxaliplatin(4) in water to give crude 1, which was followed by standing for crystallization, suction filtration, hot pure water washing and refining to obtain the final product in a purity of 99.91% and a total yield of 79%(based on 2). The contents of both 3 and oxalic acid in 1 were less than 0.05%. The quality requirements for raw material 2 in this process for synthesis of the qualified product were decreased: the content of any individual impurity in the homologous(C10-C16 acids) was no more than 0.2%, and the total impurities were no more than 1.0%. The work-up was simple, and this process was more feasible for industrial production.
  • Paper
    QIN Litai, LI Jing, XIAO Chuan, CONG Rigang
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    A new synthetic route of 2-n-propyl-4-methyl-6-(1-methylbenzimidazole-2-yl)benzimidazole(1), the key intermediate of telmisartan, was reported. n-Butyronitrile(2) reacted with MeOH or EtOH in the presence of HCl gas to give the hydrochloride salt of n-butylimide ester(3), which was followed by alkalization to obtain the free base 3. 4-Amino-3-methylbenzoic acid(4) reacted with 3 to give 4-butyrimidamido-3-methylbenzoic acid(5). Compound 5 reacted with NaClO to form an intermediate transition product, which was directly cyclized in the presence of NaOH to obtain 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid(6). Compound 6 and N-methyl-1,2-benzenediamine dihydrochloride(7) were condensed to give 1. The telescoping was used twice in this process, which simplified the operation, and the total yield of this new route was 79%(based on 4).
  • Paper
    GU Yiwen, ZUO Tiantian, ZHANG Jun, SHEN Qi
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    In this study, docetaxel(1) and photosensitizer IR820 were successfully co-loaded in poly(lacticco- glycolic acid)(PLGA)-cationic polyethyleneimine(PEI) nanoparticles(NPs) using ameliorated emulsion solvent evaporation method, in order to produce a chemo/photodynamic/photothermal therapy. IR820 was jointed with PEI via electrostatic force while 1 was enwrapped by PLGA via hydrophobic interaction. Heparin(H), a common anticoagulant, was employed to modify the nanoparticle at the surface in order to prolong the blood circulation time by charge flipping. The physicochemical properties of the co-loaded NPs(1@IR820/H NPs) were characterized, and the proliferation and metastasis of 4T1 breast cancer cells after incubation with the co-loaded NPs and irradiation with near-infrared(NIR) laser light(808 nm) were investigated. The self-assembled 1@IR820/H NPs presented a particle size of (192.7±4.1)nm and ζ potential of (-22.6±1.9)mV. Evaluations of photodynamic performance showed that enhanced cellular uptake by cationic NPs led to better photodynamic effects. The 1@IR820/H NPs showed strong inhibition on tumor cells growth in MTT assay. Furthermore, anti-metastasis effects of IR820 and the nanoparticles at cellular level were verified for the first time by our study. Downregulating matrix metalloproteinase-9(MPP-9) expression was found to be one of the pathways to inhibit the tumor metastasis via Western Blot assay.
  • Paper
    XING Wengai, LIU Xigang, CHANG Jinhua, DU Xiaojuan, LIU Cuizhe
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    The enteric-coated granules loaded with baicalin magnesium salt were prepared by high speed stirring granulation method. The formulation of particle cores was optimized by orthogonal design, then the optimal cores were coated with Eudragit L30D-55 to obtain the enteric-release effect. The accumulative amounts of the final granules were (4.12±0.62)% and (99.33±1.11)% in 0.1 mol/L hydrochloric acid and pH 6.8 medium for 2 h, respectively. The pharmacokinetic profiles of the enteric-coated granules loaded with baicalin magnesium salt or baicalin in rats were investigated. The results showed that cmax values of the baicalin magnesium salt and baicalin were (0.80±0.49) and (1.16±0.38)mg/L, AUC0→t values were (20.23±4.89) and (22.59±3.88)mg·L-1·h, respectively. There were no significant differences between two kinds of enteric-coated granules prepared by the same method, which could provide some references for the further research and development of baicalin magnesium salt.
  • Paper
    WANG Mengya, ZU Xiangyang, CHEN Fan, ZHAO Zhanqin, XUE Yun
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    The chitosan nanoparticles(CS-NPs) were prepared by ion cross-linking method, and the preparation parameters were optimized with mean diameter and polydispersion index(PDI) as indexes. The protective antigen protein Rv0180c (GLDKNKFDIRVVSPDEARRLY) in Mycobacterium tuberculosis H37Rv was synthesized according to the results of literature search. Then, the fluorescein isothiocyanate(FITC) labelled protein was encapsulated into the optimal blank CS-NPs to obtain the title nanoparticles(Pep-CS-NPs). The mean diameter, PDI and ζ potential of the blank CS-NPs were (148.13±2.24)nm, 0.197±0.013 and (+18.00±0.89)mV, respectively. No significant changes in particle size and size distribution of blank CS-NPs stored at 4 ℃ for 28 d were observed. The mean diameter, PDI, ζ potential, encapsulation efficiency and drug loading of the Pep-CS-NPs were (186.93±8.80)nm, 0.254±0.014, (+12.07±1.68)mV, (45.20±2.95)% and (12.92±1.12)%, respectively. In vitro release results showed that Pep-CS-NPs slowly released peptides and the cumulative release at 48 h was 56.6%. It was concluded that the process of preparing peptide-loaded CS-NPs by ion cross-linking method was simple, stable and mild, and the product had suitable particle size, uniform distribution and sustained-release profile, which was expected to be a new vaccine for treating tuberculosis.
  • Paper
    WANG Jiyuan, GU Liuge, QIN Yan, TAN Qiong, WEI Furong
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    A LC-MS/MS method for the determination of vortioxetine and its carboxylic acid metabolite in rat plasma was established and validated, which was applied to study the pharmacokinetics of vortioxetine and its metabolite in Sprague-Dawley rats. Deuvortioxetine was treated as an internal standard, and protein precipitation was used to extract the analytes and internal standard, which were separated on a Kromasil? C18 column. The mobile phase consisted of 10 mmol/L ammonium formate solution containing 0.1% formic acid and methanol, chromatographic separation was achieved by gradient elution at a flow rate of 0.3 ml/min for 5 min. The detection was operated using an electrospray ionization(ESI) in positive mode and the multiple-reaction monitoring mode with the transition of m/z 299.1→150.1 monitored for vortioxetine and m/z 329.2→286.3 monitored for its carboxylic acid metabolite. The mass transition of m/ z 302.3→150.0 was used to detect deuvortioxetine. The standard curves of vortioxetine and its carboxylic acid metabolite were linear in the concentration range of 0.3 - 100.0 ng/ml(r=0.998 6) and 0.9 - 300.0 ng/ml(r=0.999 2), respectively. Intra-day and inter-day RSDs of both vortioxetine and the metabolite were less than 15%. After SD rats were orally administrated of vortioxetine at 6 mg/kg, the major pharmacokinetic parameters of vortioxetine and its carboxylic acid metabolite were discovered with t1/2 of (2.66±0.35) and (1.76±0.19)h, cmax of (18.60±5.34) and (309.00±84.10)μg/L, AUC0→t of (123.0±28.9) and (1 165.0±236.0)μg·h·L-1. This method was simple, fast, sensitive and accurate, which could be used in the determination of vortioxetine and its carboxylic acid metabolite in rat plasma and pharmacokinetic studies.
  • Paper
    LIAO Ping, ZHANG Jingchen, LI Shuai, CHEN Guiliang
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    Caco-2 cell monolayer is the most commonly used cell model for drug permeability evaluation in vitro, which needs to be validated and standardized. In Combination with the relevant guidelines, some consensus recommendations on standardization of Caco-2 cell permeability measurement and evaluation are suggested based on extensive investigations of literature data and in-depth discussion with industry experts on the key technical points, and providing some references for pharmaceutical enterprises and regulatory authorities.
  • Paper
    TAN Jihua, ZHAO Tingting, PAN Hongjuan
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    A thermogravimetric analysis method was developed for the determination of gadolinium in four gadolinium contrast agents namely gadobutrol monohydrate, gadobenate dimeglumine, gadodiamide and gadolinium monoglumide. The process parameters of the thermogravimetric analysis like sample gas atomosphere and sample weight were optimized through single factor test. The optimal conditions were as follows: the flow rate of sample gas atomosphere(O2) was 60 ml/min, and temperature was increased from room temperature to 800 ℃ at the heating rate of 20 ℃/min. The results of precision test showed that the relative error and RSD of the gadolinium content determined by the optimized thermogravimetric analysis were within 2%. This paper provided a reference for the subsequent research on the determination of gadolinium content.
  • Pharmaceutical Management & Information
  • Pharmaceutical Management & Information
    ZHU Yafang, ZHANG Ziqiang, XU Cheng
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  • Pharmaceutical Management & Information
    ZENG Jie, ZHANG Rongxia, LIU Dong, JIANG Hualiang, LIU Guiming
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  • Pharmaceutical Management & Information
    CHEN Ye, DING Jinxi, HAO Li, TANG Di
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  • Pharmaceutical Management & Information
    WANG Xia, CHEN Hengqing, ZHU Jianwei
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